DESCRIPTION: Applicant's Abstract Both opioids and neuropeptides are important in modulation of the function of immune cells. Because of the common use of opioid drugs in the HIV-1 infected and other immunosuppressed individuals and AIDS patients, it is important to understand the impact of the opioids on the immune system, and more specifically, on macrophage function. We have recently demonstrated that human peripheral blood monocytes/macrophages express substance P (SP) gene and its receptor. Our preliminary experiments show that morphine enhances SP gene expression in these cells. In addition, SP suppresses LPS-induced beta-chemokine expression in primary cultures of blood monocytes and macrophages. The overall goal of our research is to determine the role of interaction of opioid and SP in the neuropathogenesis of HIV-1 infection and AIDS. The immediate goal of this proposal is to obtain data on significance of such interaction in terms of microglial cell (the resident macrophage of brain) function and HIV-1 infection of these cells. Our hypothesis is that opioids will affect HIV-1 infection of human brain-isolated microglia through neuropeptides such as SP. We propose to carry out studies to address four specific aims. First, we wish to determine whether morphine modulates the effect of SP on production of inflammatory cytokines by human microglia. Second, we wish to determine whether interaction between morphine and SP modulates production of beta-chemokines and expression of beta-chemokine receptors by human brain-isolated microglia. Third, we wish to determine whether morphine affects the expression of SP and its receptor in human brain-isolated microglia. And finally, we wish to determine whether interaction of morphine and SP modulate HIV-1 replication in human brain-isolated microglia. The results of these studies should make it possible to directly investigate the role of opioids as a cofactor in the progression of HIV-1 infection and AIDS. These studies will provide clues towards development of therapeutic strategies for HIV-1 infection and AIDS.